7-102446865-G-A

Variant names:

• chr7-102446865-G-A
• NM_001126340.3:c.578G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001126340.3(ORAI2):​c.578G>A​(p.Gly193Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ORAI2 NM_001126340.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

Genes affected

ORAI2 (HGNC:21667): (ORAI calcium release-activated calcium modulator 2) Predicted to enable store-operated calcium channel activity. Predicted to be involved in store-operated calcium entry. Predicted to be located in growth cone. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORAI2	NM_001126340.3	c.578G>A	p.Gly193Asp	missense_variant	Exon 4 of 4	ENST00000495936.7	NP_001119812.1
ORAI2	NM_001271818.2	c.578G>A	p.Gly193Asp	missense_variant	Exon 4 of 4		NP_001258747.1
ORAI2	NM_032831.4	c.578G>A	p.Gly193Asp	missense_variant	Exon 3 of 3		NP_116220.1
ORAI2	NM_001271819.2	c.347G>A	p.Gly116Asp	missense_variant	Exon 3 of 3		NP_001258748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORAI2	ENST00000495936.7	c.578G>A	p.Gly193Asp	missense_variant	Exon 4 of 4	2	NM_001126340.3	ENSP00000420178.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461266 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.578G>A (p.G193D) alteration is located in exon 4 (coding exon 2) of the ORAI2 gene. This alteration results from a G to A substitution at nucleotide position 578, causing the glycine (G) at amino acid position 193 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D;T;D;T;D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	.;D;D;.;D;.;.
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.8	M;M;.;M;.;M;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.8	.;N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0050	.;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D
Polyphen		0.63	P;P;.;P;.;P;P
Vest4		0.76
MutPred		0.82		Gain of catalytic residue at G193 (P = 0.0901);Gain of catalytic residue at G193 (P = 0.0901);Gain of catalytic residue at G193 (P = 0.0901);Gain of catalytic residue at G193 (P = 0.0901);Gain of catalytic residue at G193 (P = 0.0901);Gain of catalytic residue at G193 (P = 0.0901);Gain of catalytic residue at G193 (P = 0.0901);
MVP		0.66
MPC		2.1
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.27
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-102087312;